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rs61749721

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001110792.2(MECP2):c.799C>T(p.Arg267Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R267R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Consequence

MECP2
NM_001110792.2 stop_gained

Scores

3
2
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:39O:1

Conservation

PhyloP100: 2.35
Variant links:
Genes affected
MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 154 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-154031065-G-A is Pathogenic according to our data. Variant chrX-154031065-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031065-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.799C>T p.Arg267Ter stop_gained 3/3 ENST00000453960.7
MECP2NM_004992.4 linkuse as main transcriptc.763C>T p.Arg255Ter stop_gained 4/4 ENST00000303391.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.799C>T p.Arg267Ter stop_gained 3/31 NM_001110792.2 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.763C>T p.Arg255Ter stop_gained 4/41 NM_004992.4 P1P51608-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:39Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rett syndrome Pathogenic:20Other:1
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneNov 13, 2017- -
Pathogenic, criteria provided, single submitterclinical testing3billionJan 03, 2022Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011829, PMID:10508514). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25533962, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalOct 01, 2014- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 20, 2015This nonsense variant is predicted to cause a truncated protein, which is commonly known mechanism for disease. Variant is absent from large and broad cohorts of the ExAC project while it has been reported in at least ten RTT patients. Many clinical labs and databases classify this variant as pathogenic. Functional studies showed that variant led to deficient transcriptional repression, decreased binding to methylated DNA, and impaired microtubule stability in astrocytes. Considering all, this variant has been classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterMay 06, 2022- -
Pathogenic, criteria provided, single submitterresearchDepartment of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences-- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The stop gained p.R255* in MECP2 (NM_004992.4) has been reported reported in many individuals affected with Rett syndrome, including several de novo observations (Olivia Knight et al 2013). Experimental studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and transcriptional repression (Chloe Delepine et al, 2013; T M Yusufzai wt al 2020). The variant has been reported in ClinVar as Pathogenic/Likely Pathogenic. The p.R255* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedcase-controlMedical Genetic Institute of Henan Province, Henan Provincial People’s Hospital-- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityJun 15, 2017- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareJul 15, 2015Developmental arrest; Repeated hand to mouth movements; Microcephaly; Seizures; Normal development to 6 months of age -
Pathogenic, no assertion criteria providedclinical testingDevelopmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University-- -
Pathogenic, no assertion criteria providedclinical testingBioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare-- -
Pathogenic, criteria provided, single submitterclinical testingSeattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's HospitalNov 18, 2019- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 28, 2017A heterozygous nonsense variant was identified, NM_004992.3(MECP2):c.763C>T in exon 4 of the MECP2. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 255, NM_004992.3(MECP2):p.(Arg255*). Previous studies have shown that this results in loss of function through protein truncation (Yusufzai TM. et al, 2000). This variant is not present in the gnomAD population database and it has been previously reported multiple times in patients with Rett Syndrome (ClinVar). Additionally, functional studies showed that this variant causes loss of MECP2 transcription repression and DNA binding functions (Yusufzai TM. et al, 2000) and affects microtubule dynamics in astrocytes (Delépine C. et al,2013). Additionally, other truncating variants downstream of c.763C>T in MECP2 have been reported as pathogenic in individuals with this condition (ClinVar). Based on current information, this variant has been classified as PATHOGENIC. -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 11, 2008- -
Pathogenic, no assertion criteria providedcurationRettBASEDec 05, 2013- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Pathogenic, criteria provided, single submittercurationCentre for Population Genomics, CPGJan 09, 2024This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4)(PP4). Is a common, recurrent pathogenic variant ,identified as a de novo occurrence in at least one individual with Rett syndrome (PM6).(PMID: 20301670 , ClinVar database Variation ID: 11829) -
Likely pathogenic, criteria provided, single submitterclinical testingNeurogenetics Laboratory - MEYER, AOU MeyerNov 16, 2016- -
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San DiegoJun 19, 2020This variant is also referred to in the literature as c.763C>T (p.Arg255Ter) due to use of a different reference transcript (NM_004992.3). This nonsense variant found in exon 3 of 3 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with classic or atypical Rett syndrome (PMID: 23270700, 28135719, 17089071, 10508514, 31535341). Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype (PMID: 25634563). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.799C>T (p.Arg267Ter) variant is classified as Pathogenic. -
not provided Pathogenic:11
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaApr 03, 2015- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 17, 2016- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalOct 16, 2014- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2018- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 25, 2020Published many times in association with both classic and atypical Rett syndrome (for examples, see Hoffbuhr et al., 2001; Yamada et al., 2001; Neul et al., 2008; Lima et al., 2009); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Functional studies indicate this variant affects the protein's ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31512412, 31535341, 31139143, 30829465, 31134136, 30536762, 29655203, 30564305, 28135719, 28399682, 28263302, 26175308, 16077729, 27824329, 19722030, 18337588, 11524741, 11402105, 23238081, 10508514, 11058114, 25634563, 21575601, 23270700, 18174548) -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 16, 2018The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 10, 2021The MECP2 c.763C>T, p.Arg255Ter variant (rs61749721) induces an early termination codon and is predicted to result in a truncated protein or absent transcript. This variant is one of the most common disease causing variants of Rett syndrome (RTT) (Neul 2008), and has been associated with both classical and atypical RTT (see link to RettBASE and references therein). Functional studies showed p.Arg255Ter to be less stable in vivo and lead to deficient transcriptional repression (Yusufzai 2000). Furthermore, this variant is reported as pathogenic in ClinVar (Variation ID: 11829), and is absent from population databases (Exome Variant Server, Exome Aggregation Consortium). Therefore, this variant is considered to be pathogenic. REFERENCES Link to RettBASE: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Neul JL et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008; 70(16):1313-21. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9. -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 27, 2023- -
Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 18, 2017- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoJan 10, 2022MECP2 NM_004992.3 exon 4 p.Arg255* (c.763C>T): This variant has been reported in the literature in numerous (n>100) individuals with Rett syndrome (select publications: Amir 1999 PMID:10508514, Knight 2013 PMID:23270700, McRae 2017 PMID:28135719, Hettiarachchi 2019 PMID:31535341, RettBASE). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:11829). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In addition, functional studies have shown a deleterious effect of this variant (Yusufzai 2000 PMID:11058114, Delepine 2013 PMID:23238081, Pitcher 2015 PMID:25634563). However, these studies may not accurately represent in vivo biological function. The vast majority of pathogenic variants are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain. This variant creates a premature stop at this codon within exon 4 which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Philippe 2006 16473305). In summary, this variant is classified as pathogenic based on the data above. -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 25, 2023This sequence change creates a premature translational stop signal (p.Arg255*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 232 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 1241840, 10508514, 17089071, 23270700). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11829). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 23238081, 25634563). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg270*) have been determined to be pathogenic (PMID: 11058114, 11241840, 18174548, 23238081). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Neurodevelopmental delay Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille-- -
MECP2-Related Disorders Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego-This variant is also referred to in the literature as c.763C>T (p.Arg255Ter) due to use of a different reference transcript (NM_004992.3). This nonsense variant found in exon 3 of 3 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with classic or atypical Rett syndrome (PMID: 23270700, 28135719, 17089071, 10508514, 31535341). Loss-of-function variation in MECP2 is an established mechanism of disease (PMID: 22781840, 26942018, 31527487). Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype (PMID: 25634563). The c.799C>T (p.Arg267Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.799C>T (p.Arg267Ter) variant is classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 10, 2018The p.R255* pathogenic mutation (also known as c.763C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 763. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been detected in multiple individuals who meet classical clinical criteria for Rett syndrome and it is a commonly reported nonsense mutation in the literature (Amir RE et al. Nat. Genet. 1999 Oct; 23(2):185-8; Delépine C et al. FEBS Lett. 2013 Jan; 587(2):245-53; Fendri-Kriaa N et al. Biochem. Biophys. Res. Commun. 2011 Jun; 409(2):270-4). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
Abnormality of the nervous system Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingKariminejad - Najmabadi Pathology & Genetics CenterJul 10, 2021- -
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
Pathogenic, no assertion criteria providedcurationRettBASEDec 05, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
35
Dann
Uncertain
1.0
DEOGEN2
Benign
0.36
T
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.43
T
MetaRNN
Pathogenic
0.84
D
MutationTaster
Benign
1.0
A;A;A
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61749721; hg19: chrX-153296516; COSMIC: COSV100317851; COSMIC: COSV100317851; API